Nakata et al. SpringerPlus (2016) 5:40
DOI 10.1186/s40064-016-1679-6

Open Access

RESEARCH

The increased ratioof 11β‑hydroxysteroid dehydrogenase type 1
versus 11β‑hydroxysteroid dehydrogenase type
2 in chronic periodontitis irrespective of obesity
Takaya Nakata1, Atsuko Fujita1, Makoto Umeda1, Hiroaki Yoshida2, Kaoru Inami3, Hiroaki Masuzaki4
and Hirofumi Sawai5*

Abstract
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol, has beenreported to play an important role in metabolic diseases as well as chronic inflammatory diseases. The involvementof 11β-HSD1 in chronic periodontitis was investigated in the present study. The relationship between the levels of
11β-HSD1, chronic periodontitis, and body mass index (BMI) was analyzed. The expression of 11β-HSD1 mRNA wassignificantly higher in the chronic periodontitis group than in the control group. Since the expression of 11β-HSD2,
which converts active cortisol to inactive cortisone, was slightly lower in the chronic periodontitis group than in thecontrols, the ratio of 11β-HSD1 versus 11β-HSD2 was significantly higher in the chronic periodontitis group than in
the controls. A correlation was not observed between BMI and the level of 11β-HSD1 or between BMI and the ratio of
11β-HSD1 versus 11β-HSD2. These results suggested that an increase in the ratio of 11β-HSD1 versus 11β-HSD2 wasassociated with chronic periodontitis irrespective of obesity.
Keywords: 11β-Hydroxysteroid dehydrogenase type 1, 11β-Hydroxysteroid dehydrogenase type 2,
Chronic periodontitis, Cortisol, Obesity
Background
Cortisol, a major glucocorticoid hormone in humans,
is known to have various effects on the metabolism
of carbohydrates, fat, and proteins as well as immune
responses: briefly, it promotes the conversion of proteins and lipids into glucose, and limits and resolves the
inflammatory process (Rhen and Cidlowski 2005; Gross
and Cidlowski 2008). It has been reported that salivary
cortisol levels were positively associated with the extent
and severity of chronic periodontitis (Genco et al.1998;
Hilgert et al. 2006; Ishisaka et al. 2007; Rosania et al.
2009; Rai et al. 2011; Haririan et al. 2012; Mesa et al.
2014). With regard to serum cortisol levels, a report*Correspondence: sawai@cc.osaka‑dent.ac.jp
5Department of Internal Medicine, Osaka Dental University, 8‑1
Kuzuhahanazonocho, Hirakata, Osaka 573‑1121, Japan
Full list of author information is available at the end of the article

showed no significant differences between the chronic
periodontitis patients and the controls (Mengel et al.
2002), whereas another report demonstrated that serum
cortisol levels were significantly higher in patients withsevere periodontitis than the controls in older Japanese
adults who had never smoked (Ishisaka et al. 2008). Furthermore, it was reported that ligature-induced experimental periodontitis was more severe in Fischer 344 rats,
which mount a strong hypothalamic–pituitary–adrenal(HPA) axis response leading to the increased levels ofcorticosterone (a major glucocorticoid in rodents), thanin MHC-identical but HPA low-responding Lewis rats,suggesting the causal relationship between the increased
glucocorticoid levels and severity of periodontitis (Breivik et al. 2000, 2001).
Among the many enzymes involved in the biosynthesis and catabolism of cortisol, 11β-hydroxysteroid© 2016 Nakata et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

Nakata et al. SpringerPlus (2016) 5:40

Page 2 of 7

dehydrogenase (11β-HSD) catalyzes the conversion
between active cortisol and inactive cortisone, andis involved in the tissue-specific intracellular regulation of the actions of glucocorticoids; 11β-HSD type 1(11β-HSD1) converts inactive cortisone to active cortisol, whereas 11β-HSD type 2 (11β-HSD2) catalyzes
the opposite reaction (Livingstone et al. 2000; Seckl andWalker 2001; Tomlinson et al. 2004; Chapman et al.
2013). 11β-HSD1 is known to be abundantly expressedin adipose tissue and the liver (Tomlinson et al. 2004).
The expression of 11β-HSD1 was previously reported to
be increased in the adipocytes, especially those in visceral fat, of patients with metabolic diseases (Bujalska
et al. 1997; Rask et al. 2001; Paulsen et al. 2007). Furthermore, transgenic mice selectively overexpressing 11βHSD1 in adipose tissue showed phenotypes similar tometabolic diseases including visceral fat obesity, insulin
resistance, dyslipidemia, and hypertension (Masuzaki
et al. 2001, 2003). In contrast, 11β-HSD1-deficient mice
were protected against metabolic diseases with overnutrition (Kotelevtsev et al. 1997). Moreover, inhibitors of
11β-HSD1 have been shown to ameliorate metabolic diseases and prevent atherosclerosis in mice (Hermanowski-Vosatka et al. 2005; Nuotio-Antar et al. 2007). Thesefindings suggest that 11β-HSD1 plays a crucial role inmetabolic diseases, to which inhibitors of 11β-HSD1 may
be applied as novel therapeutics. Indeed, several highly
potent and selective 11β-HSD1 inhibitors have beendeveloped for the treatment of metabolic diseases including type 2 diabetes mellitus (Rosenstock et al. 2010; Feiget al. 2011; Anil et al. 2014; Okazaki et al. 2014; Hamilton
et al. 2015).
A relationship is known to exist between metabolic diseases and chronic periodontitis (Saito et al.
1998; Shimazaki et al. 2007; D’Aiuto et al. 2008; Morita
et al. 2010). Although the expression of 11β-HSD1 wasrecently detected in oral fibroblasts and keratinocytes(Cirillo et al. 2011), the involvement of 11β-HSD1 inchronic periodontitis has not yet been examined. We
recently reported preliminary results that the expression level of 11β-HSD1 in gingival tissues from patientswith chronic periodontitis was higher than that in thecontrols (Shiraishi et al. 2013). In the present study, we
further investigated the expression of 11β-HSD1 as well
as 11β-HSD2, and analyzed the relationships between theexpression of 11β-HSD1/2, chronic periodontitis, andobesity.

orthodontic treatments were used as controls (n = 14).
Informed consent was obtained from all individual participants (ages between 30 and 70 years) included in thisstudy. This study was approved by the Ethics Committee at Osaka Dental University on September 16, 2009
(approval number: 90921).

Methods

RT-PCR was performed using TaqMan® RNA-to-CT™
1-Step Kit and StepOnePlus™ Real Time PCR System(Applied Biosystems, Foster City, CA, USA). TaqMan®
Gene Expression Assays for 11β-HSD1 (#Hs01547870),

Participants

Periodontal tissues were obtained from patients diagnosed with chronic periodontitis (n = 38), while
those surrounding teeth extracted from patients forClinical periodontal examination

Chronic periodontitis was defined as probing depth of>3 mm, bleeding on probing, and radiographically determined alveolar bone resorption of more than one-thirdof the root of the tooth, whereas control group patients
did not have chronic periodontitis. The dentists who performed the clinical periodontal examination were themembers of the Department of Periodontology, Osaka
Dental University, and therefore they used the same
criteria for the diagnosis of chronic periodontitis. Periodontal tissues, including both epitheliums and connective tissues, were surgically removed when probing depth
after the basic periodontal treatment (including plaquecontrol, scaling, and root plaining) was ≥4 mm. Whenthe tooth mobility was class III in Miller classification
and alveolar bone resorption was more than two-thirdsof the root of the tooth at the first examination, the tooth
was extracted without the basic periodontal treatment
and periodontal tissues surrounding the extracted toothwere used for experiments.
RNA extraction

Total RNA was extracted from each sample of periodontal tissue using TRIzol Reagent (Invitrogen, Carlsbad,
CA, USA) according to the manufacturer’s protocol.
Briefly, each tissue sample of 50–100 mg was homogenized in 1 ml of the reagent, to which 0.2 ml chloroform
was added. After centrifugation at 12,000×g for 15 min
at 4 °C, the aqueous phase was transferred to a new tube.
A total of 0.5 ml isopropyl alcohol was then added andmixed. After centrifugation at 10,000×g for 10 min at
4 °C, the supernatant was removed and the RNA precipitate was washed with 1 ml of 75 % alcohol and centrifuged at 7500×g for 5 min at 4 °C. After the supernatant
was removed, the RNA pellet was air-dried and dissolved
in RNase-free water. The quantity of RNA was calculated
according to the absorbance at 260 nm, and the purity of
RNA was assessed by the spectrometric absorbance ratioat 260 nm/280 nm.
Real‑time reverse transcription (RT)‑polymerase chain
reaction (PCR)Nakata et al. SpringerPlus (2016) 5:40

Page 3 of 7

11β-HSD2 (#Hs00388669), receptor activator of nuclear
factor-κB ligand (RANKL) (#Hs00243522), receptor activator of nuclear factor-κB (RANK) (#Hs00187192), osteoprotegerin (OPG) (#Hs00171068), and glyceraldehyde
3-phosphate dehydrogenase (GAPDH) (#Hs02758991)
were purchased from Applied Biosystems (Foster City,
CA, USA). According to the manufacturer’s protocol, 1 μlof each probe was mixed with 0.5 μl of the RT Enzyme
Mix, 10 μl of the RT-PCR Mix, template (100 ng RNA),and Nuclease-free water (total volume: 20 μl). RNA wasreverse transcribed at 48 °C for 15 min followed by 95 °C
for 10 min. PCR was performed up to 45 cycles at 95 °C
for 15 s for denaturing and 60 °C for 1 min for annealing/extension. The values of 11β-HSD1, 11β-HSD2, RANKL,RANK, and OPG mRNA relative to GAPDH mRNA were
calculated in each experiment.
Body mass index (BMI)

BMI is defined as body weight (kg) divided by the squareof body height (m).
Statistical analyses

Statistical analyses were performed using SPSS software
version 21.0 (IBM, Armonk, NY, USA). The characteristics
of patients with chronic periodontitis and controls werecompared using the χ2 test for categorical variables andthe t test for continuous variables. The Mann–Whitney U
test was performed to compare mRNA expression levels
between the control group and chronic periodontitis groupor between obese and non-obese participants. Significancetesting of Spearman’s correlation coefficient between BMI
and the level of 11β-HSD1 or between BMI and the ratio of
11β-HSD1 versus 11β-HSD2 was also performed.

Results
The characteristics of the study participants are summarized in Table 1. No significant differences were observedin sex, age, height, weight, or BMI between the chronic
periodontitis group and control group.

Table 1 Characteristics of the study participantsControl group(n = 11)Periodontitis group(n = 38)

P value

No. of females/males 6/5

18/20

0.68*

Age (years)

49.1 ± 12.6

52.3 ± 11.6

0.43†

57.0 ± 13.0

60.4 ± 13.7

0.47†

Height (cm)Weight (kg)2

BMI (kg/m )163.5 ± 6.3

21.1 ± 3.3

163.8 ± 9.6

0.91†

22.3 ± 3.3

0.30†

Except where otherwise indicated, values are the mean ± SD
* χ2 test†

t test

The expression levels of 11β-HSD1 and 11β-HSD2
relative to GAPDH mRNA were analyzed using the realtime RT-PCR method. The expression levels of RANKL,RANK, and OPG mRNA were also examined, since thesemolecules are involved in osteoclast differentiation and it
was reported that the expression of RANKL was higher
and that of OPG was lower in the periodontitis groupthan healthy control (Vernal et al. 2006; Bostanci et al.
2007; Wara-aswapati et al. 2007). As shown in Fig. 1,
the values of 11β-HSD1 (Fig. 1a) and RANKL (Fig. 1c)
were significantly (P = 0.005 and P = 0.014, respectively)
higher in the periodontitis group than in the control
group. Furthermore, the values of 11β-HSD2 (Fig. 1b)
were slightly lower in the periodontitis group than in
the control group. Thus, the ratio of 11β-HSD1 versus
11β-HSD2 was significantly (P = 0.001) higher in the
periodontitis group than in the control group (Fig. 2). No
significant differences were observed in the expression
levels of RANK (Fig. 1d) and OPG (Fig. 1e) between thetwo groups.
Since correlations have already been reported between
11β-HSD1 expression and metabolic diseases (Bujalska et al. 1997; Rask et al. 2001; Paulsen et al. 2007) andbetween metabolic diseases and chronic periodontitis(Saito et al. 1998; Shimazaki et al. 2007; D’Aiuto et al.
2008; Morita et al. 2010), the relationship between theexpression of 11β-HSD1 in gingival tissues and BMI
as an index of obesity was analyzed in this study. Sincesignificance testing of Spearman’s correlation coefficient
between BMI and the level of 11β-HSD1 mRNA indicated P = 0.539 (Fig. 3a), and that between BMI and theratio of 11β-HSD1 versus 11β-HSD2 indicated P = 0.656(Fig. 3b), a correlation was not observed between BMI
and the expression of 11β-HSD1 or between BMI andthe ratio of 11β-HSD1 versus 11β-HSD2. Furthermore,no significant differences were observed in the level of
11β-HSD1 mRNA (Fig. 3c) or in the ratio of 11β-HSD1
versus 11β-HSD2 (Fig. 3d) between obese (BMI ≥ 25,
n = 9) and non-obese (BMI < 25, n = 43) participants(P = 0.171 and P = 0.887, respectively).

Discussion
In the present study, we investigated the relationshipbetween 11β-HSD1/2 and chronic periodontitis, anddemonstrated that the expression of 11β-HSD1 as wellas the ratio of 11β-HSD1 versus 11β-HSD2 was significantly increased in chronic periodontitis. To the best of
our knowledge, this is the first study to investigate theinvolvement of 11β-HSD1/2 in chronic periodontitis.
Since it has been reported that salivary and serum cortisol levels were positively associated with the extent andseverity of periodontitis (Genco et al. 1998; Hilgert et al.
2006; Ishisaka et al. 2007; Rosania et al. 2009; Rai et al.

Nakata et al. SpringerPlus (2016) 5:40

Page 4 of 7

Fig. 1 Comparison of mRNA levels in gingival tissues between the chronic periodontitis group (P) and control group (C). Box and whisker plots ofthe values of each mRNA relative to GAPDH mRNA are shown. Outliers are omitted. a 11β-HSD1; b 11β-HSD2; c RANKL; d RANK; e OPG. *P < 0.01;+
P < 0.05

2011; Haririan et al. 2012; Mesa et al. 2014; Mengel et al.
2002), the increased expression of 11β-HSD1 as well as
the increased ratio of 11β-HSD1 versus 11β-HSD2 would
result in an increase in intracellular cortisol levels, whichmight play a role in the pathophysiology of chronic
periodontitis.
Although a correlation has already been reported
between metabolic diseases and chronic periodontitis(Saito et al. 1998; Shimazaki et al. 2007; D’Aiuto et al.
2008; Morita et al. 2010), the mechanism connecting thediseases remains unclear. Although we demonstrated
that the expression of 11β-HSD1 as well as the ratio of
11β-HSD1 versus 11β-HSD2 was increased in chronic
periodontitis, a correlation was not observed between
BMI and the expression of 11β-HSD1 or the ratio of
11β-HSD1 versus 11β-HSD2, suggesting that 11β-HSD1

might play a role in chronic periodontitis irrespective ofobesity. In accordance with these results, the involvementof 11β-HSD1 in other chronic inflammatory diseases
including inflammatory bowel diseases and rheumatoid
arthritis has been reported (Zbankova et al. 2007; Hardyet al. 2008; Stegk et al. 2009). Thus, these results may
implicate 11β-HSD1 in the pathophysiology of chronic
inflammation.
Since it has been known that stress is associated withconcurrent activation of the HPA axis and that there isa relationship between stress and periodontitis, the relationships between stress, cortisol and periodontitis havebeen investigated in several studies (Genco et al. 1998;
Hilgert et al. 2006; Rosania et al. 2009; Rai et al. 2011;
Haririan et al. 2012; Mesa et al. 2014; Mengel et al. 2002).
Since 11β-HSD1 converts inactive cortisone to active

Nakata et al. SpringerPlus (2016) 5:40

Page 5 of 7

Fig. 2 Comparison of the ratio of 11β-HSD1 versus 11β-HSD2 mRNAin gingival tissues between the chronic periodontitis group (P) andcontrol group (C). Box and whisker plots of the ratio of 11β-HSD1
versus 11β-HSD2 mRNA are shown. Outliers are omitted. *P < 0.01

cortisol intracellularly, the increased expression of 11βHSD1 in chronic periodontitis seems to be independentof the HPA axis. However, further studies are required
to determine the relationship between stress and theexpression of 11β-HSD1 in chronic periodontitis.
The increased expression of RANKL in chronic periodontitis in the present study is consistent with previous findings (Vernal et al. 2006; Bostanci et al. 2007;
Wara-aswapati et al. 2007). Although the expression of
OPG was slightly increased in chronic periodontitis in
the present study, it was reduced in two previous studies(Bostanci et al. 2007; Wara-aswapati et al. 2007). Thus,
the role for OPG in chronic periodontitis remains to be
determined.
There are limitations related to this study since it is acase–control study. Moreover, there are limitations of
β error in this study due to a relatively small number ofcontrols as well as obese participants.

Conclusions
We demonstrated that the increased expression of 11βHSD1 as well as the increased ratio of 11β-HSD1 versus
11β-HSD2 was associated with chronic periodontitis.
Since a correlation was not observed between body massindex and 11β-HSD1 expression or 11β-HSD1/2 ratio,
the increased 11β-HSD1 expression or 11β-HSD1/2
ratio might play a role in the pathophysiology of chronic

Fig. 3 No significant correlation between body mass index (BMI)
and 11β-HSD1. a Scatter plot of BMI versus the expression level of
11β-HSD1 mRNA. b Scatter plot of BMI versus the ratio of 11β-HSD1
versus 11β-HSD2 mRNA. c Comparison of the level of 11β-HSD1
mRNA between obese (BMI ≥ 25) and non-obese (BMI < 25) participants. Box and whisker plots of the level of 11β-HSD1 mRNA are
shown. Outliers are omitted. d Comparison of the ratio of 11β-HSD1
versus 11β-HSD2 mRNA between obese (BMI ≥ 25) and non-obese(BMI < 25) participants. Box and whisker plots of the ratio of 11β-HSD1
versus 11β-HSD2 mRNA are shown. Outliers are omitted

periodontitis irrespective of obesity. Further investigations will be needed to elucidate the precise role of 11βHSD1/2 in chronic periodontitis.
Authors’ contributions
TN and AF carried out the RT-PCR experiments. HY and KI participated in thedesign of the study and collected samples. MU and HM participated in thedesign of the study and performed the statistical analysis. HS participatedin the design of the study, performed the statistical analysis, and drafted themanuscript. All authors read and approved the final manuscript.

Nakata et al. SpringerPlus (2016) 5:40

Author details
1
Department of Periodontology, Osaka Dental University, 8‑1 Kuzuhahanazonocho, Hirakata, Osaka 573‑1121, Japan. 2 First Department of Oraland Maxillofacial Surgery, Osaka Dental University, 8‑1 Kuzuhahanazonocho,
Hirakata, Osaka 573‑1121, Japan. 3 Department of Orthodontics, Osaka Dental
University, 8‑1 Kuzuhahanazonocho, Hirakata, Osaka 573‑1121, Japan. 4 Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology(Second Department of Internal Medicine), Graduate School of Medicine,
University of the Ryukyus, 1 Senbaru, Nishiharacho, Nakagamigun, Okinawa
903‑0213, Japan. 5 Department of Internal Medicine, Osaka Dental University,
8‑1 Kuzuhahanazonocho, Hirakata, Osaka 573‑1121, Japan.
Competing interests
The authors declare that they have no competing interests.
Funding
This study was supported by Grants-in-Aid for Scientific Research (C)(#22592105, #25462941) from Japan Society for the Promotion of Science.
Received: 2 November 2015 Accepted: 6 January 2016

References
Anil TM, Dandu A, Harsha K, Singh J, Shree N, Kumar VS, Lakshmi MN, Sunil
V, Harish C, Balamurali GV, Naveen Kumar BS, Gopala AS, Pratibha S,
Sadasivuni M, Anup MO, Moolemath Y, Venkataranganna MV, Jagannath
MR, Somesh BP (2014) A novel 11β-hydroxysteroid dehydrogenase type1
inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces
body weight in diet induced obese C57B6/J mice with a potential toprovide cardio protective benefits. BMC Pharmacol Toxicol 15:43
Bostanci N, Ilgenli T, Emingil G, Afacan B, Han B, Toz H, Berdeli A, Atilla G, McKay
IJ, Hughes FJ, Belibasakis GN (2007) Differential expression of receptor
activator of nuclear factor-κB ligand and osteoprotegerin mRNA in periodontal diseases. J Periodontal Res 42:287–293
Breivik T, Opstad PK, Gjermo P, Thrane PS (2000) Effects of hypothalamic–pituitary–adrenal axis reactivity on periodontal tissue destruction in rats. Eur J
Oral Sci 108:115–122
Breivik T, Thrane PS, Gjermo P, Opstad PK, Pabst R, von Horsten S (2001) Hypothalamic–pituitary–adrenal axis activation by experimental periodontal
disease in rats. J Periodontal Res 36:295–300
Bujalska IJ, Kumar S, Stewart PM (1997) Does central obesity reflect “Cushing’s
disease of the omentum”? Lancet 349:1210–1213
Chapman KE, Coutinho AE, Zhang Z, Kipari T, Savill JS, Seckl JR (2013) Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 inacute and chronic inflammation. J Steroid Biochem Mol Biol 137:82–92
Cirillo N, Hassona Y, Pignatelli M, Gasparoto TH, Morgan DJ, Prime SS (2011)
Characterization of a novel oral glucocorticoid system and its possible
role in disease. J Dent Res 91:97–103
D’Aiuto F, Sabbah W, Netuveli G, Donos N, Hingorani AD, Deanfield J, Tsakos
G (2008) Association of the metabolic syndrome with severe periodontitis in a large U.S. population-based survey. J Clin Endocrinol Metab
93:3989–3994
Feig PU, Shah S, Hermanowski-Vosatka A, Plotkin D, Springer MS, Donahue S, Thach C, Klein EJ, Lai E, Kaufman KD (2011) Effects of an
11β-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patientswith type 2 diabetes mellitus and metabolic syndrome. Diabetes Obes
Metab 13:498–504
Genco RJ, Ho AW, Kopman J, Grossi SG, Dunford RG, Tedesco LA (1998) Models
to evaluate the role of stress in periodontal disease. Ann Periodontol
3:288–302
Gross KL, Cidlowski JA (2008) Tissue-specific glucocorticoid action: a family
affair. Trends Endocrinol Metab 19:331–339
Hamilton BS, Himmelsbach F, Nar H, Schuler-Metz A, Krosky P, Guo J, Guo R,
Meng S, Zhao Y, Lala DS, Zhuang L, Claremon DA, McGeehan GM (2015)
Pharmacological characterization of the selective 11β-hydroxysteroid
dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes. Eur J Pharmacol 746:50–55

Page 6 of 7

Hardy R, Rabbitt EH, Filer A, Emery P, Hewison M, Stewart PM, Gittoes NJ,
Buckley CD, Raza K, Cooper MS (2008) Local and systemic glucocorticoid
metabolism in inflammatory arthritis. Ann Rheum Dis 67:1204–1210
Haririan H, Bertl K, Laky M, Rausch WD, Bottcher M, Matejka M, Andrukhov O,
Rausch-Fan X (2012) Salivary and serum chromogranin A and α-amylasein periodontal health and disease. J Periodontol 83:1314–1321
Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo
GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, Nunes CN, Olson
SH, Pikounis B, Ren N, Robertson N, Schaeffer JM, Shah K, Springer MS,
Strack AM, Strowski M, Wu K, Wu T, Xiao J, Zhang BB, Wright SD, Thieringer
R (2005) 11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 202:517–527
Hilgert JB, Hugo FN, Bandeira DR, Bozzetti MC (2006) Stress, cortisol, and periodontitis in a population aged 50 years and over. J Dent Res 85:324–328
Ishisaka A, Ansai T, Soh I, Inenaga K, Yoshida A, Shigeyama C, Awano S,
Hamasaki T, Sonoki K, Takata Y, Takehara T (2007) Association of salivary
levels of cortisol and dehydroepiandrosterone with periodontitis in older
Japanese adults. J Periodontol 78:1767–1773
Ishisaka A, Ansai T, Soh I, Inenaga K, Awano S, Yoshida A, Hamasaki T, Sonoki
K, Takata Y, Nishihara T, Takehara T (2008) Association of cortisol anddehydroepiandrosterone sulphate levels in serum with periodontal status
in older Japanese adults. J Clin Periodontol 35:853–861
Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, BestR, Brown R, Edwards CR, Seckl JR, Mullins JJ (1997) 11β-hydroxysteroid
dehydrogenase type 1 knockout mice show attenuated glucocorticoidinducible responses and resist hyperglycemia on obesity or stress. Proc
Natl Acad Sci USA 94:14924–14929
Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker
BR (2000) Understanding the role of glucocorticoids in obesity: tissuespecific alterations of corticosterone metabolism in obese Zucker rats.
Endocrinology 141:560–563
Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS(2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170
Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM,
Shinyama H, Sharp MG, Fleming S, Mullins JJ, Seckl JR, Flier JS (2003)
Transgenic amplification of glucocorticoid action in adipose tissuecauses high blood pressure in mice. J Clin Invest 112:83–90
Mengel R, Bacher M, Flores-De-Jacoby L (2002) Interactions between stress,
interleukin-1β, interleukin-6 and cortisol in periodontally diseased
patients. J Clin Periodontol 29:1012–1022
Mesa F, Magan-Fernandez A, Munoz R, Papay-Ramirez L, Poyatos R, SanchezFernandez E, Galindo-Moreno P, Rodriguez-Barranco M (2014) Catecholamine metabolites in urine, as chronic stress biomarkers, are associated with higher risk of chronic periodontitis in adults. J Periodontol
85:1755–1762
Morita T, Yamazaki Y, Mita A, Takada K, Seto M, Nishinoue N, Sasaki Y, Motohashi M, Maeno M (2010) A cohort study on the association between
periodontal disease and the development of metabolic syndrome. J
Periodontol 81:512–519
Nuotio-Antar AM, Hachey DL, Hasty AH (2007) Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. Am J Physiol Endocrinol Metab
293:E1517–E1528
Okazaki S, Takahashi T, Iwamura T, Nakaki J, Sekiya Y, Yagi M, Kumagai H, Sato
M, Sakami S, Nitta A, Kawai K, Kainoh M (2014) HIS-388, a novel orally
active and long-acting 11β-hydroxysteroid dehydrogenase type 1 inhibitor, ameliorates insulin sensitivity and glucose intolerance in diet-induced
obesity and nongenetic type 2 diabetic murine models. J Pharmacol Exp
Ther 351:181–189
Paulsen SK, Pedersen SB, Fisker S, Richelsen B (2007) 11β-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization. Obesity 15:1954–1960
Rai B, Kaur J, Anand SC, Jacobs R (2011) Salivary stress markers, stress, and periodontitis: a pilot study. J Periodontol 82:287–292
Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker
BR (2001) Tissue-specific dysregulation of cortisol metabolism in humanobesity. J Clin Endocrinol Metab 86:1418–1421
Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new
mechanisms for old drugs. N Engl J Med 353:1711–1723

Nakata et al. SpringerPlus (2016) 5:40

Rosania AE, Low KG, McCormick CM, Rosania DA (2009) Stress, depression,
cortisol, and periodontal disease. J Periodontol 80:260–266
Rosenstock J, Banarer S, Fonseca VA, Inzucchi SE, Sun W, Yao W, Hollis G, Flores
R, Levy R, Williams WV, Seckl JR, Huber R (2010) The 11-β-hydroxysteroid
dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia
in patients with type 2 diabetes inadequately controlled by metforminmonotherapy. Diabetes Care 33:1516–1522
Saito T, Shimazaki Y, Sakamoto M (1998) Obesity and periodontitis. N Engl J
Med 339:482–483
Seckl JR, Walker BR (2001) Minireview: 11β-hydroxysteroid dehydrogenase
type 1—a tissue-specific amplifier of glucocorticoid action. Endocrinology 142:1371–1376
Shimazaki Y, Saito T, Yonemoto K, Kiyohara Y, Iida M, Yamashita Y (2007)
Relationship of metabolic syndrome to periodontal disease in Japanesewomen: the Hisayama Study. J Dent Res 86:271–275
Shiraishi M, Sawai H, Nagano Y, Ueda M, Umeda M (2013) Involvement of
11β-HSD1 in metabolic syndrome and periodontal disease. J Osaka Dent
Univ 47:7–10

Page 7 of 7

Stegk JP, Ebert B, Martin HJ, Maser E (2009) Expression profiles of human
11β-hydroxysteroid dehydrogenases type 1 and type 2 in inflammatory
bowel diseases. Mol Cell Endocrinol 301:104–108
Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS,
Hewison M, Stewart PM (2004) 11β-hydroxysteroid dehydrogenase type
1: a tissue-specific regulator of glucocorticoid response. Endocr Rev
25:831–866
Vernal R, Dutzan N, Hernandez M, Chandia S, Puente J, Leon R, Garcia L, Del
Valle I, Silva A, Gamonal J (2006) High expression levels of receptor
activator of nuclear factor-kappa B ligand associated with human chronic
periodontitis are mainly secreted by CD4+ T lymphocytes. J Periodontol
77:1772–1780
Wara-aswapati N, Surarit R, Chayasadom A, Boch JA, Pitiphat W (2007) RANKL
upregulation associated with periodontitis and Porphyromonas gingivalis.
J Periodontol 78:1062–1069
Zbankova S, Bryndova J, Leden P, Kment M, Svec A, Pacha J (2007)11β-hydroxysteroid dehydrogenase 1 and 2 expression in colon frompatients with ulcerative colitis. J Gastroenterol Hepatol 22:1019–1023